Diabetes mellitus (DM) and Alzheimer's disease (AD) are expanding health problems. Recent evidence suggests that these diseases may be related, at least in some patients, and that DM may influence the initiation or progression of AD. Epidemiological and biochemical data suggest the nature of specific metabolic alterations in brain by which this may occur. The experiments described in this application will test the hypothesis that age, inherited susceptibilities to environmental factors, and DM combine to augment brain oxidative damage and neurodegeneration in the absence of stroke. The Specific Aims proposed are (1) to determine brain oxidative damage, AGE formation, neurodegeneration, and complications of cerebrovascular disease in various models of experimental DM in young and old rodents alone and in combination with models of age-related oxidative damage to brain; (2) to determine whether interventions that suppress oxidative stress and/or AGE formation are effective at limiting brain oxidative damage, AGE formation, neurodegeneration, and cerebrovascuiar disease in models developed in Specific Aim 1; and (3) determine oxidative modifications on tau in cerebrospinal fluid (CSF) of probable AD patients to develop biomarkers for use with experimental therapies such as those investigated in Specific Aim 2. The candidate's immediate career goal is to redirect his area of research from cancer genetics and biology to the study of AD and related dementias. Specifically, the candidate will be instructed in methods of analysis of the chemical pathology of oxidized lipids and proteins in brain tissue and other biological samples. He will apply his understanding of genetic models of disease to studies that explore complex relations between genetic and environmental factors in the generation of oxidative damage to brain. The program developed in this application will allow him to integrate the training and experience he has received to date with the neuropathology training he is now undertaking to become a creative, productive, and independent physician/scientist focused on the mechanisms of age-related dementing illnesses.